Selected Articles from This Issue

Cutaneous melanoma metastasis begins with lymphatic invasion, followed by hematogenous dissemination and distant organ metastasis. While Rodríguez, Castro Pérez, Setaluri, and co-authors have shown that exchange protein directly activated by cAMP (EPAC) drives growth and survival in primary melanoma tumors but not metastatic lesions, underlying signaling dynamics remain unclear. In this study, the investigators used genetically matched primary and metastatic melanoma cells and pharmacological and genetic EPAC modulation to query EPAC-regulated signaling in each case. The authors found that a pharmacological EPAC inhibitor, ESI-09, abrogates expression of cyclins, cyclin-dependent kinases (CDK), and CDK inhibitors uniquely in primary melanoma cells, and correspondingly disrupts cell cycle progression only in primary melanoma cells. Mechanistically, the authors demonstrated that while EPAC-mediated RAP1 activation and EPAC subcellular localization are similar in primary and metastatic melanoma cells, EPAC inhibition affects AKT and mTORC1 signaling and downstream metabolic features in primary but not metastatic cells. All together,...